As there is no truly effective treatment or vaccine against AIDS, preventive measures are the only tools that can presently reduce the transmission of human immunodeficiency virus (HIV). The consistent and careful use of appropriate condoms represents an effective barrier to prevent HIV transmission. However, condoms should be used for almost all sexual intercourses to significantly reduce the probability of acquiring infection. In Africa, the most intensive prevention programs were only able to increase condom use to approximately 70% of all sexual intercourses in female prostitutes. Thus, doubts arise about the possibilities of condom promotion in controlling the AIDS epidemic in high risk groups. In situations where heterosexual transmission of HIV is important, preventive measures that depend on female behaviour would be an additional tool to control the epidemic. Since the women's compliance to preventive interventions for sexually transmitted diseases (STDs) is superior to that of men, regular use of such a preventive measure may be possible. This is reinforced by the fact that the introduction of different products into the vagina is a common practice in developing countries. Such a protective tool may also be useful in male homosexual relations as it could provide additional protection under the control of the receptive partner.
The development of microbicides to prevent the sexual transmission of HIV in humans constitutes actually one of the most important research areas in the field of HIV prevention. One of the major difficulties with this approach is that drugs used to control HIV transmission, including spermicides such as nonoxynol-9, have been shown to induce local inflammation and ulcerations which might favour the entry of HIV. As the number of individuals infected with HIV is growing dramatically throughout the world, there is an urgent need to develop active products and/or vehicles that could reduce the transmission of HIV with minimal mucosal irritation and minimal effects on the vaginal flora and pH. The use of gel formulations of microbicides or any other drug, that could be topically applied to the vaginal, cervical and/or ano-rectal mucosae of humans, represents a convenient strategy to achieve such a goal. The microbicides or any other drug can be entrapped into the gel formulations either as free or encapsulated into drug carriers such as liposomes, nanoparticles or cyclodextrins. Such microbicidal gels could prolong the local microbicidal activity, eliminate local irritation and reduce systemic side effects of incorporated active agents.
Herpes simplex virus type 2 (HSV-2) is one of the most common STDs. An animal model of intravaginal HSV-2 infection represents an interesting approach to evaluate the efficacy of our gel formulations to prevent the sexual transmission of that pathogen. Another important herpes virus infection is herpes simplex virus type 1 (HSV-1) which is a neurotropic virus that infects principally the neuroectodermal tissues including the skin, the peripheral nerves and the central nervous system. Recurrent HSV-1 cutaneous infections are frequently observed in immunocompromised patients. Zoster is clinically characterized by an unilateral dermatome distribution and by the occurrence of neuralgic pain both as a result of peripheral nerve involvement. Although, it is a mild disease, cutaneous HSV infections can be troublesome, especially for patients with frequent episodes. Foscarnet and acyclovir are both antiviral agents active against all types of herpes viruses. However, the currently available treatments, either topical or systemic, have only a limited efficacy particularly for the treatment of symptomatic recurrent herpes. Therefore, there is a need to develop new topical formulations of antiviral agents which could improve the efficacy of drugs.
Liposomes are microscopic vesicles composed of one or several lipid bilayers separated by aqueous compartments in which a variety of drugs can be incorporated. Numerous studies have shown an improved therapeutic index and a reduced toxicity for drugs entrapped in liposomes. We have already demonstrated that the encapsulation of anti-HIV agents into liposomes allows high cellular penetration, good in vitro antiviral activity against HIV, efficient targeting of macrophage-rich tissues and a marked improvement of the pharmacokinetics of drugs (Desormeaux et al., 1994, AIDS 8:1545-1553; Makabi-Panzu et al., 1994, AIDS Res. Hum. Retroviruses 10:1463-1470; Dusserre et al., 1995, AIDS 9:833-841; Harvie et al., 1995, AIDS 9:701-707; Harvie et al., 1996, Antimicrob. Agents Chemother. 40:225-229). To our knowledge, liposome-encapsulated drugs have never been used to prevent the mucosal transmission of infectious agents. When applied locally to mucosa or skin, liposomes are usually taken up by monocytes and macrophages and also by Langerhans cells which may capture and harbor HIV. Consequently, in contrast with free drugs, which tend to diffuse rapidly through the mucosa and reach the circulation, the use of drugs within liposomes and incorporated into a gel formulation should concentrate the active agents within infected cells as well as within cells susceptible to HIV infection. Such drug delivery system is even more attractive as it was shown that liposomes are very well tolerated when given topically (Parnham and Wetzig, 1993, Chem. Phys. Lipids 64:263-274).
U.S. Pat. No. 5,292,516 describes gel formulations comprising poloxamers which are used as drug delivery systems. However, no mention is made in that reference that the gels themselves are physical barriers per se impeding permeation of pathogens therethrough.
The international patent publication WO 95/10268 describes a composition comprising poloxamer 407 gel (18% w/w) containing cysteamine to prevent HIV infection. This reference indeed teaches that poloxamer 407 gel can be used as a vaginal gel, but it does not suggest that the poloxamer itself might be used as a physical barrier to prevent the transmission of a pathogen and its permeation through the membrane of mucosa. Furthermore, this reference does not teach that the gel formulation could act as a pharmacological barrier to prevent the infection of host cells. In addition, this reference does not show any in vitro and in vivo evidence that the gel formulation might be efficient to prevent the transmission of pathogens.
There is, therefore, still a need for a method and compositions for preventing transmission of pathogens through the membrane of mucosae and/or skin which compositions and method would result in the creation of a physical barrier to permeation of pathogens, and optionally in the further creation of a chemical or pharmacological barrier to pathogen transmission.